Multi-Omics Reveals Dysregulated Neurotransmitter Systems in Aging and CNS Disorders

Area of Science:

• Neuroscience
• Genomics
• Computational Biology

Background:

• Neurotransmitter systems (NTS) are implicated in various diseases, but their composition in aging and different disorders remains unclear.
• Understanding NTS alterations is crucial for identifying disease mechanisms and therapeutic targets.

Purpose of the Study:

• To integrate multi-omics data, including single-nucleus RNA sequencing (snRNA-seq), to identify disease-associated NTS.
• To comprehensively characterize NTS cellular heterogeneity in aging and neuropsychiatric disorders.
• To explore the relationship between age, sex, and disease-associated NTS.

Main Methods:

• Integration and analysis of 368 snRNA-seq datasets from 17 cohort studies, comprising over 1 million cells from the human prefrontal cortex.
• Construction of an NTS and regulatory gene module to identify disease-discriminatory signals.
• Comparative analysis of disease-related cerebral organoids and parental brain tissues.

Main Results:

• Creation of a large-scale snRNA-seq dataset for the human prefrontal cortex, covering healthy aging and eight neuropsychiatric disorders.
• Comprehensive description of NTS cellular heterogeneity across the lifespan and in disease states.
• Identification of a disease-associated NTS module with validation from protein-level and external datasets.
• Partial similarity observed between patient-derived organoids and parental brain tissues.

Conclusions:

• The study provides a multi-disease cell atlas of the human brain, detailing NTS heterogeneity in aging and disease.
• Findings offer new insights into the mechanisms of central nervous system (CNS) diseases.
• The research highlights potential for precision NTS-targeted therapies for CNS disorders.